This application is a request for a NIAAA Mentored Patient-Oriented Research Career Development Award (K23) award. It is estimated that approximately 14% of men and 5% of women in the United States will experience the symptoms of alcohol abuse or dependence over their lifetime, with an economic cost of about $185 billion/year. Aberrant hypothalamic-pituitary-adrenal (HPA) axis function may contribute to vulnerability for alcohol use disorders by sensitizing mesolimbic dopamine neurons involved in reward. Similar to that of alcohol abuse vulnerability, the heritability of cortisol responses to stress has been estimated to be high. [unreadable] [unreadable] Endogenous opioids not only regulate mesolimbic dopamine and thus alcohol-induced reinforcement, but also modulate cortisol response to stress. Thus, an abnormality in the endogenous opioid system may simultaneously provoke aberrant cortisol responses to stress and aberrant dopamine responses to alcohol induced reward. Based on these interactions, this research plan proposes to employ the cold pressor test (CRT), a pain stressor which activates both endogenous opioid and HPA axis activity. [unreadable] [unreadable] The study will determine whether family history of alcoholism (Specific Aim #1) and haplotypes in the mu-opioid receptor (MOR) gene (Specific Aim #2) are associated with cortisol responses to the CPT among healthy young adults. The analysis will take into account demographic and psychosocial confounders. If successful, then this research may lead to further knowledge of the interactions between the endogenous opioid system and the HPA axis. It is hoped that such knowledge will contribute to future pharmacogenetic approaches in the screening and management of alcohol abuse disorders. The candidate's career development plan is set in a multidisciplinary environment and includes the following: conducting mentored research in the project described above, developing expertise in human subjects research techniques, acquiring experience in the application of psychological assessment scales, learning relevant laboratory techniques, and gaining skills in [unreadable] genetic analyses. The candidate's long term career goal is to become an independent clinical investigator in the field of alcohol use disorders. Specifically, the candidate aspires to make significant contributions to understanding the neuroendocrinology of alcohol abuse and dependence and its translational application to treating these disorders. [unreadable] [unreadable] [unreadable]